Epilepsy is a disease characterized by epileptic seizures—generally defined as those seizures caused by a brief disruption of brain function involving temporary abnormal electrical activity in the nerve cells. The location of this disruption in the brain determines the type of seizure. Epilepsy should be contrasted with syncope which, although both frequently result in unconsciousness, syncope refers to a loss of consciousness due to transient impairment of cerebral blood flow.
The two main types of epileptic seizures are partial and generalized. Partial seizures involve part of the brain, while generalized seizures involve the whole brain. Partial seizures can become generalized seizures if the epileptic activity spreads to the whole brain.
Many people are born with epilepsy. In other cases, epilepsy develops as a result of brain damage from other disorders. For example, brain tumors, head injury, alcoholism, and Alzheimer's disease frequently lead to epilepsy because they alter the normal workings of the brain. Strokes, heart attacks, and other conditions that deprive the brain of oxygen also can cause epilepsy in some cases. About 32% of all newly developed epilepsy in elderly people appears to be due to cerebrovascular disease. Meningitis, AIDS, viral encephalitis, and other infectious diseases can lead to epilepsy, as can hydrocephalus—a condition in which excess fluid builds up in the brain.
Epileptiform activity usually begins in vivo with excessive AMPA receptor activation; as the seizure activity intensifies, an increased involvement of NMDA receptors is observed (Dingledine, McBain, Basic Neurochemistry. Philadelphia, Pa.: Lippincott-Raven; 1998, 315-333). Over activation of NMDA and AMPA receptors allows excessive Ca2+ influx into the cell resulting in activation of many enzymes and proteases, which begin to destroy the components of the cell membrane. That includes different Ca++ activated enzymes, including calmodulin-dependent protein kinase, calcineurin, calpain, PKS, phospholipase and number of endonucleases (Whetsell J. Neuropathol. Exp. Neurol. 1996; 55:1-13).
Seizures from epilepsy can take a number of forms. Generalized seizures include “tonic-clonic,” “absence,” “atonic,” and “mytonic” seizures. A tonic-clonic seizure is the classic and most visible type of seizure associated with epilepsy and refers to a seizure in which the patient loses consciousness, the body stiffens, the patient falls to and experiences jerking movements, “Absence” seizures are generally characterized by momentary unconsciouness; “atonic” seizures are characterized by sudden loss of muscle control that causes person to fall to the ground); and “mytonic” seizures are characterized by brief forceful jerks by the whole body or part of it. Partial seizures are generally classified as “simple partial” (symptoms include twitching; numbness; sweating; dizziness; nausea; disturbances to hearing, vision, smell or taste; strong sense of déjà vu), or “complex partial” (the person appears aware when in fact he/she is not). It is often difficult to distinguish between these types of seizures in the clinic because rarely does the seizure occur in the doctor's office, and the patient usually has no memory of the seizure.
A single seizure, or even a plurality of seizures, does not mean that the person has epilepsy. Many young children have seizures that are not technically caused by epilepsy, such as convulsions from fevers. Other types of non-epileptic seizures are caused by an imbalance of body fluids or chemicals, prenatal brain impairment, or are associated with other disease states such as heart conditions and diabetes. These non-epileptic seizures are often referred to as “pseudo-epilepsy.” They are often difficult to distinguish from epileptic seizures because of the multitude of forms that a seizure can take. Seizures can also often be caused by a condition known as non-epileptic attack disorder (“NEAD”). Seizures occurring in this condition are psychogenic in nature, and do not have a physical origin.
There are number of different procedures, including electroencephalogram (EEG) and brain scans (i.e. computed tomography) to determine whether a person has epilepsy and, if so, what kind of seizures the person has. Even with these advanced procedures, it is often very difficult to accurately differentiate between epilepsy and non-epilepsy, or to distinguish between the different types of epileptic seizures. Individuals suffering from pseudo-epilepys are often diagnosed as having epilepsy based upon EEG testing, and paroxysmal discharges observed in these patients during the test period. Among seizure patients who display abnormal paroxysmal discharges during testing, a method is needed for distinguishing between epilepsy and non-epilepsy.
Up-to-now there has been an unmet diagnostic need for an in vitro diagnostic test for distinguishing epilepsy from pseudo-epilepsy. There has also been an unmet diagnostic need for evaluating the risk of a person developing epilepsy, and for improved targeting, monitoring and adjustment of therapeutic regimens such as anticonvulsant medication and neurosurgery that are directed against epilepsy.